The invention relates to corticoid 17,21-dicarboxylic esters and corticoid 17-carboxylic ester 21-carbonic esters of the formula I: 
in which:
A is CHOH and CHCl in arbitrary steric arrangement, CH2, Cxe2x95x90O or 9(11) double bond,
Y is hydrogen, fluorine or chlorine,
Z is hydrogen, fluorine or methyl,
R(1) is optionally substituted or fused aryl or hetaryl
(C1-C4)-alkyl is saturated, unsaturated once or more than once, branched by further alkyl groups, unsubstituted or inserted or substituted by heteroatoms O, S or N,
n is zero or 1,
m is zero or 1,
R(2) is linear or branched (C1-C8)-alkyl 
R(3) is hydrogen or xcex1- or xcex2-methyl.
Corticoid 17,21-dicarboxylic esters and corticoid 17-carboxylic ester 21-carbonic esters of the formula I are preferred in which:
R(1), A, Y, Z and R(3) are defined as above,
R(2) is linear or branched (C1-C8)-alkyl 
The invention also relates to a process for preparing a compound I, in which process
a) a compound of the formula II: 
in which R(5) is OH and the remaining substituents have the abovementioned meanings,
a1) is reacted with an activated carboxylic acid of the formula III, preferably a halide or anhydride or azolide,
R(6)-COxe2x80x94(O)nxe2x80x94[(C1-C4)-alkyl]m-R(1)xe2x80x83xe2x80x83III
in which:
n is zero,
m is zero or 1, and
[(C1-C4)-alkyl] and R(1) have the abovementioned meanings, and
R(6) is Cl, Br, O[xe2x80x94COxe2x80x94(O)nxe2x80x94](C1-C4)-alkyl]m-R(1)1, xe2x80x94Oxe2x80x94C(O)CF3, or another activated acid radical, or
a2) is reacted with a haloformate of the formula III, in which
n is 1,
m is zero or 1,
[(C1-C4)-alkyl] and R(1) have the abovementioned meanings and R(6) is Cl, Br or I, or
a3) is reacted with a carboxylic acid of the formula III itself, in which
R(6) is OH, and
n is zero,
and the other substituents are given in formula III, in the presence of water-eliminating reagents (DCCI, etc.),
or in which
b) compounds of the formula II: 
in which R(5) is Br, I, or a sulfonic aryl ester group or sulfonic alkyl ester group, and the other substituents have the meaning given in formula I, are reacted with a salt, preferably a K or Na salt or a trialkylammonium salt, of a carboxylic acid of the formula III:
R(6)-COxe2x80x94(O)nxe2x80x94[(C1-C4)-alkyl]m-R(1)xe2x80x83xe2x80x83III
in which
R(6) is xe2x80x94[Oxe2x88x92Me+], and
n is zero,
and the other substituents have the meanings given in formula III,
Me preferably being the cation of an alkali metal salt or of a trialkylammonium salt.
The steroid 17-carboxylic esters with a free 21-hydroxyl group of the formula II [R(5)=OH], which are required as starting substances, are as a rule known or are prepared by known methods.
The stippled line between carbon atoms 1 and 2 indicates that this bond can be a single bond or an unsaturated bond.
The steroid 17-carboxylic esters with R(5) being Br, I, xe2x80x94OSO2-aryl or xe2x80x94OSO2-alkyl in formula II are known as a rule or are prepared by known methods, e.g. in analogy with corresponding corticoid 17-alkyl carbonate 21-compounds in accordance with U.S. Pat. No. 4,377,575 (HOE 78/F 082) and EP-A-470 617 (HOE 90/F 241). The 17-carboxylic esters of the following corticosteroids come into consideration in this context:
prednisolone, prednisone, 6xcex1-methylprednisolone, 6xcex1,61xcex1-dimethylprednisolone, 16xcex1-methylprednisolone, hydrocortisone (cortisol), cortisone, 6xcex1-methylcortisol, Reichstein""s substance S, 11-desoxy-9(11)-dehydroprednisolone, 6xcex1-fluoroprednisolone, dexamethasone, 6xcex1-fluorodexamethasone, 9xcex1-fluoroprednisolone, 6xcex1,9xcex1-difluoroprednisolone, 6xcex1-methyl-9xcex1-fluoroprednisolone, betamethasone and clobetasol.
The carboxylic acids of the formula III [R(6) is OH and n is zero] which are used as reaction partners, and their activated derivatives, such as the halides [R(6)xe2x95x90Cl, Br or I, or their anhydrides], or their azolides [R(6) is imidazolide or triazolide], or their salts [R(6) is (MeO)xe2x80x94, preferably (KO)xe2x80x94 or (NaO)xe2x80x94], are as a rule known and are prepared, where appropriate, by general preparative methods. Examples of carboxylic acids according to formula III [R(6) is OH and n is zero] which can be used in accordance with the invention are to be found in the list at the end of the text prior to the claims.
All carboxylic acids coming into this category carry, in their acid radical, an aryl or hetaryl group which is optionally substituted by methylenedioxy, halogen, alkyl, alkoxyl, acyl, thioalkyl, thioacyl, nitro, amino, aminoalkyl, amido, cyano, oxyacyl, oxyaryl, etc., or is optionally fused. The aryl and hetaryl groups are essential constituents of the invention.
As is demonstrated in the pharmacological section, corticoid 17,21-dicarboxylic esters of this type (=21-aryl ester or 21-hetaryl ester type), in particular, often exhibit qualities of effect which are clearly superior, as regards the local/systemic ratio of antiinflammatory effect, to those of structurally related corticoid 17,21-dicarboyxlic esters or structurally related corticoid 17-alkyl carbonate 21-carboxylic esters which do not carry any aryl or hetaryl group in the 21-acid residue.
Detailed description of the conduct of the individual reactions in the processes for preparing the products according to Formula I according to the invention:
Regarding process variant a:
In order to prepare 21-carboxylic esters of the abovementioned type, either carbonyl halides or carboxylic azolides of the formula IV
R(6)-OCxe2x80x94[(C1-C4-alkyl]m-R(1)xe2x80x83xe2x80x83IV,
in which:
R(6) is Cl, Br, I, 
m is zero or 1, and
R(1) and (C1-C4)-alkyl have the meanings given for formula III,
or carboxylic anhydrides of the formula V:
O{xe2x80x94OCxe2x80x94[(C1-C4)-alkyl]m-R(1)}2xe2x80x83xe2x80x83V,
in which
m is zero or 1, and
R(1) and (C1-C4)-alkyl have the meanings given for formula III, are preferably used. In both cases, the carboxylic acids on which they are based, and which are given in the list, can be used, preferably their carbonyl chlorides, carboxylic anhydrides, carboxylic imidazolides and carboxylic triazolides.
R(6) in formula IV can also comprise other groups which activate the carboxyl group in carboxylic acids for esterification, such as, for example, xe2x80x94Oxe2x80x94COxe2x80x94CF3, or the activated carboxylic acids which can be prepared from phosphonic or phosphinic anhydrides (e.g. propylphosphonic anhydride) or polyphosphoric anhydride (PPA).
Additional phosphorus reagents which can bring about mild esterification of organic carboxylic acids with the 21-alcohol group of corticoid 17-alkyl carbonates are cited or described in the literature references Synth. Commun. 13, 471 ff (1983) and Synth. Commun. 14, 515 ff (1984).
In order to carry out the esterification using a carbonyl halide or carboxylic anhydride or a haloformate, the steroid component is dissolved in an inert solvent, for example in an ether, such as dioxane, tetrahydrofuran or diglyme, or in optionally halogenated hydrocarbons, such as benzene, toluene, cyclohexane, methylene chloride or chloroform, or in acetone, or in a mixture of these solvents. In order to remove the hydrohalic acid which is produced in the reaction, 1 to 1000 molar equivalents of a tertiary base, such as pyridine, quinoline, triethylamine, dimethylaniline, dimethylaminopyridine, etc., are added. However, an inorganic base, such as sodium hydrogen carbonate or calcium carbonate, can also be used for removing the acid. 1 to 200 molar equivalents, preferably 1-3 molar equivalents, of one of the above-listed acylating agents, optionally dissolved in one of the above-listed solvents, are then added dropwise at a temperature of xe2x88x9240xc2x0 C. up to the boiling point of the solvent used, preferably at a temperature of 0xc2x0 C. to 25xc2x0 C. Subsequently, the reaction mixture is left to stand for one to 120 hours at a temperature of xe2x88x9240xc2x0 C. up to the boiling point of the solvent, preferably at a temperature of 0xc2x0 C. to 25xc2x0 C.
When using carboxylic anhydrides as acylating agents, it is now and then advantageous not to add solvents. As a rule, it is sufficient simply to add the organic base preferably pyridine, to the acid anhydride, which may optionally be used in excess.
Particularly in the case of sensitive (and sometimes unstable) carboxylic acid derivatives of the abovementioned type, in particular when using phenylacetyl chlorides or anhydrides and hetarylacetyl chlorides and anhydrides, it is of great preparative advantage, and of great advantage with regard to the selectivity of the reaction, if the corticoid 17-carboxylic esters having a free 21-hydroxyl group are reacted with 1 to 4 molar equivalents of the chloride or anhydride at xe2x88x9210xc2x0 to +6xc2x0 C. (maximum 20xc2x0 C.) in chlorinated hydrocarbons, such as, preferably, dichloromethane, and with 1 to 4 molar equivalents of a pyridine base, preferably dimethylaminopyridine. Under these circumstances, the reaction products of the formula I are obtained in high purity, with negligible quantities of byproducts, in particular 11-acylated products (monitoring of the course of the reactions with TLC), that is the reactions are highly regioselective with regard to conversion of the 21-hydroxyl group.
In the case of the reactions with carbonyl chlorides, absolute dioxane or tetrahydrofuran is frequently advantageously added to the reaction mixture, e.g. in the case of benzoyl chloride, where, e.g., the ratio of dioxane/pyridine is approximately 1:1; in addition, in order to accelerate the reaction, the reaction mixture is often, particularly in the case of sterically hindered or less reactive carbonyl chlorides or carboxylic anhydrides, heated to about 60xc2x0 C. (monitoring of the course of the reaction with TLC).
The reaction products can be characterized using thin layer chromatography (TLC); in this context, the reaction products have RF values of about 0.65 to 0.8. As a rule, the reaction products are characterized by mass spectra using MS=m/z= . . . (M+H+) (FAB spectra, as a rule); the monoisotopic molar masses are registered in each case. The M+H+ values were rounded up in each case. IR spectra, 1H-NMR spectra and UV spectra can also be enlisted for the characterization.
For the working up, the reaction mixture is poured into water, to which sodium chloride and sodium bicarbonate may, where appropriate, have been added, in association with which the reaction products generally precipitate out in crystalline form, frequently only after standing for some length of time. Oily or waxy reaction products are concentrated by extracting, while shaking, with a suitable extracting agent, and then evaporating. If necessary, the reaction products can be fractionated or purified by recrystallization or by chromatography. Intensive digestion in an organic solvent which either does not dissolve the reaction product or else dissolves it as little as possible, for example diethyl ether or cyclohexane, or a mixture of these components, may also frequently suffice for the further purification of the reaction products.
When using carboxylic azolides, the esterification is expediently carried out as a one-pot reaction. In this case, arylacetic acid or hetarylacetic acid, for example, or another carboxylic acid of the formula III [R(6) is OH, n is zero], is dissolved in absolute pyridine, and a preferably equimolar quantity of N,N-carbonyldiimidazole or N,N-carbonyl[1H-1,2,4-triazole] is added, with the corresponding acid azolides forming at 0xc2x0 to 20xc2x0. After adding an approximately equimolar quantity of corticoid 17-carboxylic ester of the formula II [R(5)xe2x95x90OH] and a catalytic quantity of a base, preferably sodium hydride or sodium imidazolide, the mixture is stirred in pyridine at between 0xc2x0 and 40xc2x0 C., preferably 20xc2x0, and then worked up in the customary manner.
However, the carboxylic azolide, which has previously been prepared in absolute tetrahydrofuran with equimolar quantities of N,Nxe2x80x2-carbonylazolide and carboxylic acid, and then isolated, can also be added to the steroid dissolved, in solvents such as pyridine, dimethylformamide or tetrahydrofuran, with the subsequent procedure being as described above [see also Chem. Ber. 95, pp. 1284 ff. (1962)].
When esterifying with the aid of phosphonic or phosphinic anhydrides, equimolar quantities of carboxylic acid and corticoid 21-alcohol in absolute pyridine are preferably added to 50% strength propanephosphoric anhydride in methylene chloride at 20xc2x0 to 60xc2x0 C., while also adding 4-dimethylaminopyridine as an acid-capturing agent, with the working up being carried out as usual (pouring into ice water, extracting with ethyl acetate, washing with 5% KHSO4, distilling off and crystallizing). Polyphosphoric anhydride (PPA) may also be employed instead of phosphonic anhydrides.
An additional advantageous esterification process, which is applicable to the carboxylic acids according to formula III [R(6) is OH and n is zero] or included in the list, is the direct reaction of corticoid 17-carboxylic esters of the formula II [R(5) is OH] using water-removing agents such as carbodiimides, preferably N,Nxe2x80x2-dicyclohexylcarbodiimide (DCCI). In some cases, xe2x80x9cmolecular sievesxe2x80x9d can also be used as water-removing agents in place of DCCI.
The esterification can be catalytically accelerated or optimized by adding an acid, e.g. sulfuric acid, phosphoric acid, hydrochloric acid, diphenylphosphoric acid or p-toluene sulfonic acid, or their pyridinium salts, or an organic base, for example, dimethylaminopyridine (=particularly advantageous in halogenated solvents, for example, methylene chloride, or in dimethylformamide), something which is very advantageous, particularly in the case of carboxylic acids, e.g. of the indolylacetic acid, pyrrolecarboxylic acid, arylacetic acid and hetarylacetic acid types, etc., which are either sensitive or otherwise only react with difficulty. In this context, it is surprising that the secondary 11-hydroxyl group in the corticoid 17-carboxylic esters which are employed is not (practically) as a rule esterified simultaneously, as is occasionally observed when esterifying with the corresponding acid halides.
In a particular variant of the process, a catalytic quantity of the pyridinium salt of sulfuric acid is added to a solution of one molar equivalent of corticoid 17-carboxylic ester 21-alcohol [formula II, R(5) is OH] and 1 to 4 molar equivalents, preferably 2 equivalents, of carboxylic acid of the formula III [R(6) is OH and n is zero] in absolute pyridine, and this is followed, after about 20 min., by the addition of 1 to 4 molar equivalents, preferably 1 to 2 molar equivalents, of dicyclohexylcarbodiimide. The mixture is then stirred at 0xc2x0 to 50xc2x0 C., preferably 20xc2x0 C., until a sample examined by TLC indicates that the starting carboxylic acid has disappeared and that only desired carboxylic acid 21-corticoid esters of the formula I are present. The dicyclohexylurea which has formed is filtered off and the filtrate is then expediently poured into water; this is then followed by filtration (in the case of crystal formation) or decantation (in the case of oily or waxy precipitates), washing with water (where appropriate, extraction can also take place with extracting agents, in particular dichloromethane), drying, and recrystallization as usual; alternatively, if required, the reaction products are purified by customary chromatography, preferably on silica gel.
Instead of pyridine, other inert solvents, such as, for example, tetrahydrofuran, dioxane, methylene chloride or dimethylformamide, expediently with the addition of tertiary bases, for example pyridine or 4-dimethylaminopyridine, can also be used in some cases. The latter solvents are to be preferred when molecular sieves are used as water-removing agents.
In addition to this, the following variant has proved valuable for esterifying with the sensitive arylacetic acids and heterylacetic acids: 1 equivalent of carboxylic acid is dissolved at 0xc2x0 C. in absolute dichloromethane, and 1 equivalent of DCCI, up to 0.2 equivalent of 4-N,Nxe2x80x2-dimethylaminopyridine and a solution of 1 equivalent of corticosteroid 17-carboxylic ester 21-alcohol in absolute dichloromethane are then added in succession and the mixture is stirred at 20xc2x0 C. for 18 to 48 hours. After the customary working up, the desired ester of the formula I can be obtained in pure form. A molecular sieve can also be used instead of DCCI.
In a further esterification method, 1 molar equivalent of carboxylic acid and trifluroacetic anhydride are added to corticoid 17-carboxylic ester 21-[tert-butyldimethylsilyl-(O)-ether] in absolute tetrahydrofuran, and the customary working up takes place after stirring at 20xc2x0 C. for about 1 to 6 hours.
However, the carboxylic acid and the corticoid 17-carboxylic ester 21-alcohol (free form) can also be reacted directly with trifluoroacetic anhydride to give the desired 21-carboxylic ester (=formation of the mixed anhydride from carboxylic acid and trifluoroacetic acid, which anhydride then reacts with the 21-alcohol to give the 21-ester).
Regarding process variant b:
A further advantageous process variant, which leads to the corticoids according to the invention, comprises heating a corticoid 17-carboxylic ester 21-halide, preferably 21-iodide or 21-bromide, or 21-sulfonate, preferably 21-p-chlorobenzene sulfonic ester or 21-methane sulfonic ester, with the metal salts, preferably alkali metal salts or trialkylammonium salts, of the carboxylic acids included in list 2, in inert organic solvents, preferably dimethyl sulfoxide, dimethylformamide, 2-butanone, acetone or acetonitrile, at 20xc2x0 C. up to the boiling points of the solvents used, preferably at about 50xc2x0 C., for 1 to 16 hours, preferably 1 to 10 hours, and isolating after the customary working up, preferably pouring in water, filtering or decanting off the precipitate, and customary purification.
In connection with this nucleophilic reaction in which a 21-halide or 21-sulfonic ester group is exchanged for a carboxylic ester group, it is surprising that, under the preferably alkaline reaction conditions, the 17-carboxylic ester group, which is jointly responsible for the activity profile, is not simultaneously saponified in the process products.
The compounds I prepared according to procedures a) and b) are such that a hydroxyl group in the 11 position can, where appropriate, be oxidized to the keto group by customary methods. This oxidation is preferably carried out using chromium trioxide in an acid medium and in an inert organic solvent. A 9(11) double bond which is present in the corticoid moiety can, where appropriate, be converted by adding hydrohalic acid or by chlorine, in accordance with the usual known methods, into the corresponding corticoid 17,21-dicarboxylic esters according to the invention having a 11xcex2-hydroxyl, 9xcex1-halide group (9xcex1F,Cl) or 11xcex2,9xcex1-dichloro group.
The process products possess valuable pharmacological properties. They have, in particular, a very strong local and topical antiinflammatory action, and some of them exhibit, surprisingly, a very good ratio of local to systemic antiinflammatory effect, which ratio is often markedly superior, as can be deduced from pharmacological standard tests to that of analogous corticoid 17,21-diesters, and, for example to that of known corticoid 17-alkyl carbonate 21-esters, which do not carry any aryl or hetaryl group in the 21-ester radical, such as, for example, 21-ester groups having a 21-alkyl group. Accordingly, an agent for treating inflammatory dermatoses and comprising a compound of the formula I is also a subject of the invention.
The process products can be used in veterinary and human therapy in the form of suspensions, ointments, creams, sprays, etc., for treating inflammatory dermatoses of a wide variety of origins. In this context, it is to be emphasized as being particularly advantageous for the local and topical forms of therapy that, owing to their extremely favorable ratio of local to systemic antiinflammatory effect, even in the case of lengthy therapy at high dosage rates, the process products are able in practice only to elicit trivial systemic side effects. In the case of external treatment, ointments, creams, suspensions, etc. are used at a concentration of 0.01 to 2% by weight. In particular, the process products exhibit a split (ratio) of local/systemic antiinflammatory effects in pharmacological tests which is sometimes appreciably better than that of corresponding preparations having a 21-ester group lacking aryl or hetaryl moieties, as are found in the compounds according to the invention, in the ester moiety. In addition, some of the process products also exhibit a more powerful local antiinflammatory action than do the abovementioned analog preparations. In addition to this, the corticoid 17,21-dicarboyxlic esters according to the invention can often have a still lower atrophoderma-generating effect than do the abovementioned analogous corticoid 17,21-diesters, which is a further advantage for their use in dermatotherapeutic treatment.
Corticoid 17-carboxylic ester 21-cinnamic esters, in particular those substituted in the 4-position in the aromatic moiety by methoxy, methylenedioxy or ethoxy, can, by way of their antiinflammatory effect, possess an additional sunscreen effect against solar radiation, in particular UV-B and UV-A radiation. The same also applies to corticoid 17-carboxylic acid 21-esters which have a N,N-dialkyl benzoate, preferably a 4-(dimethylamino)-benzoate, in the 21-position. These compounds, too, can possess an additional sunscreen effect. Furthermore, corticoid 17-carboxylic esters having a chlorambucil moiety in the 21-ester, as, for example, prednisolone 17-n-butyrate 21-chlorambucil ester, can have antitumorigenic effects which correspond to the effects of the known prednimustine (Merck Index 11, 7718).
In addition to this, the process products according to the invention can be combined in pharmaceutical formulations with diverse antibiotics which are locally active and which are well tolerated by the skin, e.g. of the gentamycin, neomycin, erythromycin or tetracycline type, or of the fusidic acid type, and others. Such combinations of the process products and the locally active antibiotics can be used for treating primary bacterial, or bacterially superinfected, inflammatory dermatoses.
Pharmacological Experimental Section
Thus, prednisolone 17-benzoate 21-phenylacetic ester (I) or betamethasone 17-benzoate 21-phenylacetic ester (II), for example, exhibited a strong local antiinflammatory effect in association with a strikingly favorable split to weak systemic activity, as is evident from the pharmacological test results recorded below [preparation for comparison, prednicarbate (=prednisolone 17-ethyl carbonate 21-propionate (U.S. Pat. No. 4,242,334) and (Merck Index 11, 7717))]:
1. Local antiinflammatory effect in rat croton oil ear edema following epicutaneous application
We used the rat ear method of Tonelli et al., Endocrinology, 77, 625 (1965): male Wistar rats from our own colony and weighing about 50 g were treated epicutaneously on the right ear with the irritant or with irritant containing test substance. The left ear remained untreated. TPA (12-o-tetradecanoylphorbol 13-acetate, SIGMA P 8139) dissolved in acetone, 0.2 mg/ml, (of which 20 xcexcl each on the inside and outside) was used for eliciting the inflammation. The corticoids under examination were dissolved in this solution in the given final concentrations. Controls only received the TPA/solvent mixture. The animals were sacrificed using CO2 4 h after the epicutaneous treatment. Disks measuring 8 mm in diameter were punched out of the right (treated) and the left (untreated) ears and weighed immediately.
This difference, as the parameter for the degree of inflammation, was set at 100 in the controls (mg, xxc2x1s). The antiinflammatory effect is characterized by giving the dose in mg/ml which is required for approximately 50% inhibition:
2 a) Examining for systemic antiinflammatory effect in the xe2x80x9cantiinflammatory effect following subcutaneous administration: Carrageenan paw edema in ratsxe2x80x9d test.
The carrageenan paw edema test in rats in accordance with the method described by Winter et al., Proc. Soc. exp. Biol. (New York) 111, 544 (1962) was chosen as the test for the acute systemic antiinflammatory effect. Male Sprague-Dawley rats of about 120 g in weight were given the substances to be tested s.c. (0.2 ml/100 g) dissolved in sesame oil. 30 min later, 0.1 ml of a 0.5% carrageenan solution was injected into the left hind paw. 6 hours later, the degree of swelling was measured volumetrically. Controls were only given sesame oil.
The paw volumes are given in ml, xxc2x1s. In this case too, the antiinflammatory effect is characterized by giving the dose in mg/kg required for approximately 50% inhibition.
2 b) Examining for systemic effect: gluconeogenesis in rats
A sensitive method for detecting systemic effects on carbohydrate metabolism is to examine the gluconeogenic effect of corticosteroids in the adrenalectomized rat.
Three days prior to the experiment, groups of in each case 6 rats are adrenalectomized under pentobarbital anesthesia and provided with 0.9% sodium chloride solution as drinking fluid. Two days later, i.e. 24 hours before initiating the experiment, the feed is removed in order to reduce the glycogen stores in the liver.
On the day of the experiment, the preparations under examination are administered subcutaneously, dissolved in sesame oil (2 ml/kg). Six hours later, the animals are decapitated, and in each case the liver is removed and 1 g thereof is taken up in 5 ml of 0.6 molar perchloric acid. After homogenization, the free glucose is measured in the supernatant from the centrifugation, while the centrifugation sediment (centrifugate; glycogen) is cleaved enzymically with amyloglucosidase, after which the glucose content is also measured in this fraction (Hexokinase method, Boehringer Mannheim). The following results were obtained (average valuexc2x1standard deviation):
It is evident from the above results for the new formation of glucose and glycogen that compounds I and II still do not have any significant effect at 0.3 mg/kg whereas prednicarbate is already exhibiting a small but significant (p less than 0.05, t test) effect at this concentration. A similar situation pertains in relation to the 3 mg/kg dosages, where prednicarbate has a significantly stronger effect than do compounds I and II. The therapeutic advantage (low systemic effect) is therefore greater in the case of the compounds I and II than it is in the case of prednicarbate.
Furthermore, the compounds prednisolone 17-n-butylcarboxylic ester 21-phenyl acetate and betamethasone 17-n-valerate 21-phenyl acetate, for example, also exhibit similar effect profiles to those of compounds I and II.